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2.  Association Between Unprotected Ultraviolet Radiation Exposure and Recurrence of Ocular Herpes Simplex Virus 
American Journal of Epidemiology  2013;179(2):208-215.
Studies have suggested that exposure to ultraviolet (UV) light may increase risk of herpes simplex virus (HSV) recurrence. Between 1993 and 1997, the Herpetic Eye Disease Study (HEDS) randomized 703 participants with ocular HSV to receipt of acyclovir or placebo for prevention of ocular HSV recurrence. Of these, 308 HEDS participants (48% female and 85% white; median age, 49 years) were included in a nested study of exposures thought to cause recurrence and were followed for up to 15 months. We matched weekly UV index values from the National Oceanic and Atmospheric Administration to each participant's study center and used marginal structural Cox models to account for time-varying psychological stress and contact lens use and selection bias from dropout. There were 44 recurrences of ocular HSV, yielding an incidence of 4.3 events per 1,000 person-weeks. Weighted hazard ratios comparing persons with ≥8 hours of time outdoors to those with less exposure were 0.84 (95% confidence interval (CI): 0.27, 2.63) and 3.10 (95% CI: 1.14, 8.48) for weeks with a UV index of <4 and ≥4, respectively (ratio of hazard ratios = 3.68, 95% CI: 0.43, 31.4). Though results were imprecise, when the UV index was higher (i.e., ≥4), spending 8 or more hours per week outdoors was associated with increased risk of ocular HSV recurrence.
PMCID: PMC3873108  PMID: 24142918
cohort studies; herpes simplex virus; recurrence; sunlight; ultraviolet light; UV index
3.  Cervical Neoplasia-Related Factors and Decreased Prevalence of Uterine Fibroids among a Cohort of African-American Women 
Fertility and sterility  2013;101(1):10.1016/j.fertnstert.2013.09.021.
To investigate whether the previously reported inverse association between cervical neoplasia and uterine fibroids is corroborated.
Cross-sectional analysis of enrollment data from an ongoing prospective study of fibroid development.
Detroit, Michigan area.
Self-reported data on abnormal Pap smear, colposcopy and cervical treatment were obtained from 1,008 African-American women ages 23-34 with no previous fibroid diagnosis and no reported history of HPV vaccination. Presence of fibroids was assessed at a standardized ultrasound examination.
Main Outcome Measure(s)
The association between the 3 cervical neoplasia-related variables and presence of fibroids was evaluated with logistic regression to estimate age-adjusted and multivariable-adjusted odds ratios (ORs).
Of the analysis sample, 46%, 29% and 14% reported a prior abnormal Pap smear, colposcopy and cervical treatment, respectively. Twenty-five percent had fibroids at ultrasound. Those reporting cervical treatment had a 39% [aOR: 0.61, 95%CI (0.38-0.96)] reduction in fibroid risk. Weak non-significant associations were found for abnormal Pap smear and colposcopy.
Although a protective-type association of cervical neoplasia with uterine fibroids seems counter intuitive, a causal pathway is possible, and the findings are consistent with two prior studies. Further investigation is needed on the relationship between fibroids and cervical neoplasia and HPV-related mechanisms.
PMCID: PMC3880401  PMID: 24268705
Uterine Fibroids; Cervical Neoplasia; Cervical Treatment; Abnormal Pap Smear; Colposcopy
4.  Genetic diversity is a predictor of mortality in humans 
BMC Genetics  2014;15(1):159.
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4301661  PMID: 25543667
Heterozygosity; Human; Survival; GWAS
5.  Testing Departure from Additivity in Tukey’s Model using Shrinkage: Application to a Longitudinal Setting 
Statistics in medicine  2014;33(29):5177-5191.
While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey’s one degree of freedom (df) model for non-additivity treats the interaction term as a scaled product of row and column main effects. Due to the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency and the corresponding test could lead to increased power. Unfortunately, Tukey’s model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey’s and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies — the Normative Aging Study and the Multi-Ethnic Study of Atherosclerosis.
PMCID: PMC4227925  PMID: 25112650
adaptive shrinkage estimation; gene-environment interaction; longitudinal data; Tukey’s one df test for non-additivity
6.  The diversity of human papillomavirus infection among human immunodeficiency virus-infected women in Yunnan, China 
Virology Journal  2014;11(1):202.
Yunnan has one of the oldest and the most severe human immunodeficiency virus (HIV) epidemics in China. We conducted an observational study to evaluate the human papillomavirus (HPV) genotype distribution in relation to cervical neoplastic disease risk among HIV-infected women in Yunnan.
We screened 301 HIV-infected non-pregnant women in Mangshi prefecture in Yunnan province. All consenting participants underwent simultaneous and independent assessment by cervical cytology, colposcopy-histopathology, and HPV genotyping. Unadjusted and multivariable-adjusted multinomial logistic regression analysis was conducted to evaluate factors associated with single or multiple carcinogenic HPV genotypes.
HPV genotypes were present in 43.5% (131/301) overall, and carcinogenic HPV genotypes were present in 37.5% (113/301) women. Among women with carcinogenic HPV genotypes, 80 (70.8% of 113) had a single carcinogenic HPV type, while 33 (29.2%) women had multiple (2 or more) carcinogenic HPV types. Overall, the most common carcinogenic HPV types were HPV52 (7.3%), HPV58 (6.6%), HPV18 (6.3%), HPV16 (6.0%), and HPV33 (5.3%). In women with cervical precancerous lesions (i.e., high-grade squamous intraepithelial lesions [HSIL] on cytology or cervical intraepithelial neoplasia grade 2 or worse [CIN2+] detected on colposcopy-histology), the most commonly detected genotypes were HPV16 (28.6%), HPV52 (25.0%), HPV58 (17.9%), HPV18 (10.7%) and HPV31 (10.7%). Increasing age was an independent risk factor associated with presence of single carcinogenic HPV types (adjusted odds ratio: 1.04, 95%CI: 1.01-1.07, p = 0.012) but not with the presence of multiple carcinogenic types in the multivariable-adjusted models.
As HIV-infected women continue to live longer on antiretroviral therapy in China, it will be increasingly important to screen for, and prevent, HPV-associated cervical cancer in this population, especially given the wide diversity and multiplicity of HPV genotypes.
PMCID: PMC4279793  PMID: 25481842
HPV; Genotypes; HIV; Cervix; China
7.  Multiplexed Digital mRNA Profiling of the Inflammatory Response in the West Nile Swiss Webster Mouse Model 
Background and purpose
The ability to track changes in gene expression following viral infection is paramount to understanding viral pathogenesis. This study was undertaken to evaluate the nCounter, a high throughput digital gene expression system, as a means to better understand West Nile virus (WNV) dissemination and the inflammatory response against WNV in the outbred Swiss Webster (SW) mouse model over the course of infection.
The nCounter Mouse Inflammation gene expression kit containing 179 inflammation related genes was used to analyze gene expression changes in multiple tissues over a nine day course of infection in SW mice following intraperitoneal injection with WNV. Protein expression levels for a subset of these cytokine/chemokine genes were determined using a multiplex protein detection system (BioPlex) and comparisons of protein/RNA expression levels made.
Expression analysis of spleen, lung, liver, kidney and brain of SW mice infected with WNV revealed that Cxcl10 and Il12b are differentially expressed in all tissues tested except kidney. Data stratification of positively confirmed infected (WNV (+)) versus non-infected (WNV (−) tissues allowed differentiation of the systemic inflammatory gene response from tissue-specific responses arising from WNV infection. Significant (p<0.05) decrease in C3ar1 was found in WNV (−) spleen. Il23a was significantly upregulated, while Il10rb was down-regulated in WNV (−) lung. Il3 and Mbl2 were down-regulated in WNV (−) liver. In WNV (+) livers, Stat1, Tlr2, chemokines Cxcl1, Cxcl3, Cxcl9, Cxcl10, cytokines Il6, Il18, cytokine-related gene Il1r and cytokine agonist Ilrn were significantly upregulated. In WNV (−) brain tissues, Csf2 and Cxcl10 were significantly upregulated. Similar gene and protein expression kinetics were found for Ccl2, Ccl3, Ccl4 and Ccl5 and correlated with the presence of infectious virus. In summary, the utility of the nCounter platform for rapid identification of gene expression changes in SW mice associated with WNV infection was demonstrated.
Author Summary
The nCounter, a high throughput digital molecular detection and quantitation system, was used to define the inflammatory response of SW mice to WNV infection following intraperitoneal injection in multiple tissues over a 9 day course of viral infection. Data analysis identified expression profiles common and unique to major tissues. Complementary protein suspension array analysis of a subset of genes demonstrated the expression kinetics of RNA and protein expression compared to infectious virus production. Data stratification of WNV (+) versus WNV (−) tissues allowed differentiation of the systemic inflammatory gene response versus tissue-specific responses due to infection with WNV over time. The results generated from this study will allow for further hypothesis generation and testing.
PMCID: PMC4207670  PMID: 25340818
8.  Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women 
PLoS ONE  2014;9(10):e108934.
Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations.
From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels.
Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L).
IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more.
PMCID: PMC4186782  PMID: 25285521
9.  The Role of Valvular Endothelial Cell Paracrine Signaling and Matrix Elasticity on Valvular Interstitial Cell Activation 
Biomaterials  2014;35(11):3596-3606.
The effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100μm thin poly(ethylene glycol) (PEG) hydrogels of 3 to 27 kPa Young’s moduli were fabricated in transwell inserts. VICs were cultured on the gels, as VIC phenotype is known to change significantly within this range, while VlvECs lined the underside of the membrane. Co-culture with VlvECs significantly reduced VIC activation to the myofibroblast phenotype on all gels with the largest percent decrease on the 3 kPa gels (~70%), while stiffer gels resulted in approximately 20–30% decrease. Additionally, VlvECs significantly reduced αSMA protein expression (~2 fold lower) on both 3 and 27 kPa gels, as well as the number (~2 fold lower) of nodules formed on the 27kPa gels. Effects of VlvECs were prevented when nitric oxide (NO) release was inhibited with L-NAME, suggesting that VlvEC produced NO inhibits VIC activation. Withdrawal of L-NAME after 3, 5, and 7 days with restoration of VlvEC NO production for 2 additional days led to a partial reversal of VIC activation (~25% decrease). A potential mechanism by which VlvEC produced NO reduced VIC activation was studied by inhibiting initial and mid-stage cGMP pathway molecules. Inhibition of soluble guanylyl cyclase (sGC) with ODQ or protein kinase G (PKG) with RBrcGMP or stimulation of Rho kinase (ROCK) with LPA, abolished VlvEC effects on VIC activation. This work contributes substantially to the understanding of the valve endothelium’s role in preventing VIC functions associated with aortic valve stenosis initiation and progression.
PMCID: PMC4040249  PMID: 24462357
10.  Disease pathways at the Rat Genome Database Pathway Portal: genes in context—a network approach to understanding the molecular mechanisms of disease 
Human Genomics  2014;8(1):17.
Biological systems are exquisitely poised to respond and adjust to challenges, including damage. However, sustained damage can overcome the ability of the system to adjust and result in a disease phenotype, its underpinnings many times elusive. Unraveling the molecular mechanisms of systems biology, of how and why it falters, is essential for delineating the details of the path(s) leading to the diseased state and for designing strategies to revert its progression. An important aspect of this process is not only to define the function of a gene but to identify the context within which gene functions act. It is within the network, or pathway context, that the function of a gene fulfills its ultimate biological role. Resolving the extent to which defective function(s) affect the proceedings of pathway(s) and how altered pathways merge into overpowering the system’s defense machinery are key to understanding the molecular aspects of disease and envisioning ways to counteract it. A network-centric approach to diseases is increasingly being considered in current research. It also underlies the deployment of disease pathways at the Rat Genome Database Pathway Portal. The portal is presented with an emphasis on disease and altered pathways, associated drug pathways, pathway suites, and suite networks.
The Pathway Portal at the Rat Genome Database (RGD) provides an ever-increasing collection of interactive pathway diagrams and associated annotations for metabolic, signaling, regulatory, and drug pathways, including disease and altered pathways. A disease pathway is viewed from the perspective of networks whose alterations are manifested in the affected phenotype. The Pathway Ontology (PW), built and maintained at RGD, facilitates the annotations of genes, the deployment of pathway diagrams, and provides an overall navigational tool. Pathways that revolve around a common concept and are globally connected are presented within pathway suites; a suite network combines two or more pathway suites.
The Pathway Portal is a rich resource that offers a range of pathway data and visualization, including disease pathways and related pathway suites. Viewing a disease pathway from the perspective of underlying altered pathways is an aid for dissecting the molecular mechanisms of disease.
PMCID: PMC4191248  PMID: 25265995
Molecular pathway; Disease pathway; Altered pathway; Ontology; Systems biology
11.  A contrast between children and adolescents with excellent and poor control: the T1D exchange clinic registry experience 
Pediatric diabetes  2013;15(2):110-117.
Optimizing glycemic control in pediatric type 1 diabetes (T1D) is essential to minimizing long-term risk of complications. We used the T1D Exchange database from 58 US diabetes clinics to identify differences in diabetes management characteristics among children categorized as having excellent vs. poor glycemic control.
Among registry participants 6–17 yr old with diabetes duration ≥2 yr, those with excellent control [(A1c <7%)(53 mmol/mol) (N= 588)] were compared with those with poor control [(A1c ≥9%) (75 mmol/mol) (N = 2684)] using logistic regression.
The excellent and poor control groups differed substantially in diabetes management (p < 0.001 for all) with more of the excellent control group using insulin pumps, performing blood glucose monitoring ≥5×/d, missing fewer boluses, bolusing before meals rather than at the time of or after a meal, using meal-specific insulin:carbohydrate ratios, checking their blood glucose prior to giving meal time insulin, giving insulin for daytime snacks, giving more bolus insulin, and using a lower mean total daily insulin dose than those in poor control. After adjusting for demographic and socioeconomic factors, diabetes management characteristics were still strongly associated with good vs. poor control. Notably, frequency of severe hypoglycemia was similar between the groups while DKA was more common in the poorly controlled group.
Children with excellent glycemic control tend to exhibit markedly different diabetes self-management techniques than those with poor control. This knowledge may further inform diabetes care providers and patients about specific characteristics and behaviors that can be augmented to potentially improve glycemic control.
PMCID: PMC4164957  PMID: 23957219
blood glucose self-monitoring; diabetes mellitus; insulin; pediatric; type 1 diabetes mellitus
Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6–12 months. Repeat HPV testing at 12 month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.
PMCID: PMC3707974  PMID: 22961444
human papillomavirus; HPV; duration; persistence; clearance; natural history; repeat testing; literature review; screening; cervical cancer; meta-analysis
13.  The Impact of Sustained Engagement on Cognitive Function in Older Adults: The Synapse Project 
Psychological science  2013;25(1):103-112.
In the research reported here, we tested the hypothesis that sustained engagement in learning new skills that activated working memory, episodic memory, and reasoning over a period of 3 months would enhance cognitive function in older adults. In three conditions with high cognitive demands, participants learned to quilt, learned digital photography, or engaged in both activities for an average of 16.51 hr a week for 3 months. Results at posttest indicated that episodic memory was enhanced in these productive-engagement conditions relative to receptive-engagement conditions, in which participants either engaged in nonintellectual activities with a social group or performed low-demand cognitive tasks with no social contact. The findings suggest that sustained engagement in cognitively demanding, novel activities enhances memory function in older adulthood, but, somewhat surprisingly, we found limited cognitive benefits of sustained engagement in social activities.
PMCID: PMC4154531  PMID: 24214244
cognitive aging; intervention; engagement; cognitive training; aging cognition; episodic memory; cognitive reserve; working memory
14.  The relationship between diastolic blood pressure and coronary artery calcification is dependent on single nucleotide polymorphisms on chromosome 9p21.3 
BMC Medical Genetics  2014;15:89.
Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity.
As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study’s Offspring Cohort (N = 1,140).
We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455).
Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.
PMCID: PMC4168694  PMID: 25185447
Epidemiology; Genetics of cardiovascular disease; Atherosclerosis risk factors; Other arteriosclerosis
15.  Bullous Lesions in a Patient with Systemic Lupus Erythematosus 
Bullous eruptions in patients with lupus erythematosus can be difficult to diagnose as bullous lesions can develop in lupus-specific lesions, and primary blistering disorders can also occur. Additionally, these patients tend to have multiple co-morbidities making them more likely to be on many medications that can lead to bullous drug reactions. A thorough history, the clinical presentation, and histopathological findings along with direct immunofluorescence can be helpful in diagnosing most cases. The authors report the case of a woman with a long history of systemic lupus erythematosus who initially presented in their clinic for diagnosis and management of erythema dyschromicum perstans and one year later developed bullae in atypical targetoid lesions on the extremities and trunk. They discuss several blistering disorders that have been reported in patients with lupus erythematosus with a focus on features that help distinguish erythema multiforme, fixed drug eruption, and lupus erythematosus from Stevens-Johnson syndrome/toxic epidermal necrolysis. In the patient described herein, the authors favor a diagnosis of Stevens-Johnson syndrome, but the classification between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis cannot be made in some cases.
PMCID: PMC4174920  PMID: 25276277
16.  Contaminated Heparin and Outcomes after Cardiac Surgery: A Retrospective Propensity-Matched Cohort Study 
PLoS ONE  2014;9(8):e106096.
During 2007 and 2008 it is likely that millions of patients in the US received heparin contaminated (CH) with oversulfated chondroitin sulfate, which was associated with anaphylactoid reactions. We tested the hypothesis that CH was associated with serious morbidity, mortality, intensive care unit (ICU) stay and heparin-induced thrombocytopenia following adult cardiac surgery.
Methods and Findings
We conducted a single center, retrospective, propensity-matched cohort study during the period of CH and the equivalent time frame in the three preceding or the two following years. Perioperative data were obtained from the institutional record of the Society of Thoracic Surgeons National Database, for which the data collection is prospective, standardized and performed by independent investigators. After matching, logistic regression was performed to evaluate the independent effect of CH on the composite adverse outcome (myocardial infarction, stroke, pneumonia, dialysis, cardiac arrest) and on mortality. Cox regression was used to determine the association between CH and ICU length of stay. The 1∶5 matched groups included 220 patients potentially exposed to CH and 918 controls. There were more adverse outcomes in the exposed cohort (20.9% versus 12.0%; difference = 8.9%; 95% CI 3.6% to 15.1%, P<0.001) with an odds ratio for CH of 2.0 (95% CI, 1.4 to 3.0, P<0.001). In the exposed group there was a non-significant increase in mortality (5.9% versus 3.5%, difference = 2.4%; 95% CI, −0.4 to 3.5%, P = 0.1), the median ICU stay was longer by 14.1 hours (interquartile range −26.6 to 79.8, S = 3299, P = 0.0004) with an estimated hazard ratio for CH of 1.2 (95% CI, 1.0 to 1.4, P = 0.04). There was no difference in nadir platelet counts between cohorts.
The results from this single center study suggest the possibility that contaminated heparin might have contributed to serious morbidity following cardiac surgery.
PMCID: PMC4146562  PMID: 25162640
17.  Sequencing at sea: challenges and experiences in Ion Torrent PGM sequencing during the 2013 Southern Line Islands Research Expedition 
PeerJ  2014;2:e520.
Genomics and metagenomics have revolutionized our understanding of marine microbial ecology and the importance of microbes in global geochemical cycles. However, the process of DNA sequencing has always been an abstract extension of the research expedition, completed once the samples were returned to the laboratory. During the 2013 Southern Line Islands Research Expedition, we started the first effort to bring next generation sequencing to some of the most remote locations on our planet. We successfully sequenced twenty six marine microbial genomes, and two marine microbial metagenomes using the Ion Torrent PGM platform on the Merchant Yacht Hanse Explorer. Onboard sequence assembly, annotation, and analysis enabled us to investigate the role of the microbes in the coral reef ecology of these islands and atolls. This analysis identified phosphonate as an important phosphorous source for microbes growing in the Line Islands and reinforced the importance of L-serine in marine microbial ecosystems. Sequencing in the field allowed us to propose hypotheses and conduct experiments and further sampling based on the sequences generated. By eliminating the delay between sampling and sequencing, we enhanced the productivity of the research expedition. By overcoming the hurdles associated with sequencing on a boat in the middle of the Pacific Ocean we proved the flexibility of the sequencing, annotation, and analysis pipelines.
PMCID: PMC4145072  PMID: 25177534
Genomics; Sequencing; Expeditions; Metagenomics; Environmental microbiology; Coral reef; Vibrio
18.  Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice 
Journal of Virology  2014;88(4):1914-1923.
Machupo virus (MACV) is the etiological agent of Bolivian hemorrhagic fever (BHF), a reemerging and neglected tropical disease associated with high mortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and high mortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates.
PMCID: PMC3911560  PMID: 24284323
19.  Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure 
Pain  2013;154(8):1419-1426.
Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity six weeks after two common trauma exposures. The study included data from two prospective emergency department-based cohorts: a discovery cohort (n=949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n=53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain six weeks after trauma exposure were assessed using a 0–10 numeric rating scale. After adjustment for multiple comparisons, six FKBP5 polymorphisms showed significant association (minimum p <0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain six weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent post-traumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.
PMCID: PMC3699900  PMID: 23707272
21.  Rift Valley fever virus MP-12 vaccine encoding Toscana virus NSs retains neuroinvasiveness in mice 
The Journal of General Virology  2013;94(Pt 7):1441-1450.
Rift Valley fever is a mosquito-borne zoonotic disease endemic to sub-Saharan Africa. Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) causes high rates of abortion and fetal malformation in pregnant ruminants, and haemorrhagic fever, neurological disorders or blindness in humans. The MP-12 strain is a highly efficacious and safe live-attenuated vaccine candidate for both humans and ruminants. However, MP-12 lacks a marker to differentiate infected from vaccinated animals. In this study, we originally aimed to characterize the efficacy of a recombinant RVFV MP-12 strain encoding Toscana virus (TOSV) NSs gene in place of MP-12 NSs (rMP12-TOSNSs). TOSV NSs promotes the degradation of dsRNA-dependent protein kinase (PKR) and inhibits interferon-β gene up-regulation without suppressing host general transcription. Unexpectedly, rMP12-TOSNSs increased death in vaccinated outbred mice and inbred BALB/c or C57BL/6 mice. Immunohistochemistry showed diffusely positive viral antigens in the thalamus, hypothalamus and brainstem, including the medulla. No viral antigens were detected in spleen or liver, which is similar to the antigen distribution of moribund mice infected with MP-12. These results suggest that rMP12-TOSNSs retains neuroinvasiveness in mice. Our findings demonstrate that rMP12-TOSNSs causes neuroinvasion without any hepatic disease and will be useful for studying the neuroinvasion mechanism of RVFV and TOSV.
PMCID: PMC3709633  PMID: 23515022
22.  Factors Associated With Adherence to Follow-up Colposcopy 
Understanding the gaps in knowledge about human papilloma virus (HPV) infection, transmission, and health consequences and factors associated with the knowledge gap is an essential first step for the development of interventions to improve adherence to follow-up among women with abnormal Pap smears.
To examine the relationship between knowledge about HPV and adherence to scheduled colposcopic evaluation and variables related to lack of knowledge among women with abnormal Pap tests.
Telephone surveys were conducted with women who attended their scheduled appointments (adherers) and women who did not attend their appointments (nonadherers).
The multivariable analyses indicate that lower HPV knowledge was independently associated with nonadherence to follow-up, controlling for race and education level. Factors related to lower knowledge scores included non-white race, lower education, and lack of health insurance at the time of the scheduled appointment.
Lack of knowledge of HPV was related to nonadherence among women scheduled for colposcopic evaluation.
Translation to Health Education Practice
Health education interventions that deliver complex information about HPV and cervical cancer should be in a format that is accessible and understandable to the women who are most at risk of being nonadherent.
PMCID: PMC4075768  PMID: 24991653
23.  Challenges and Recommendations to Recruiting Women Who Do Not Adhere to Follow-Up Gynecological Care 
Non-adherence to recommended follow-up visits after an abnormal cytological finding is associated with poorer outcomes and higher health care costs. The purpose of this paper is to describe the challenges when examining reasons for non-adherence to cervical cancer screening follow-up and to discuss the recommendations to overcome those challenges.
We conducted a telephone survey with two subgroups of women: 1) those which adhered to recommended follow-up care after an abnormal Pap test, and 2) those which did not adhere.
The follow-up accrual among non-adherent women lagged behind that of adherers. We were able to contact and conduct a survey with 51% of the adherers and 26% of the non-adherers. The challenges in studying non-adherent women were related to several distinct factors: 1) the definition of non-adherence, 2) the availability of alternate contact information, 3) the amount and type of financial incentives, and 4) the availability of staffing. We describe strategies employed to increase the accrual of non-adherent women.
This paper describes four recommendations that may play a role in understanding and reducing non-adherence to follow-up gynecological care.
PMCID: PMC4075769  PMID: 24991485
Non-Adherence; Patient Compliance; Cervical Cancer; Cervical Intraepithelial Neoplasia; Cancer Screening; Abnormal Pap Smear; Abnormal Pap Test; HPV; Patient Navigation
24.  Assessment of High-Risk Human Papillomavirus Infections Using Clinician- and Self-Collected Cervical Sampling Methods in Rural Women from Far Western Nepal 
PLoS ONE  2014;9(6):e101255.
Nepal has one of the highest cervical cancer rates in South Asia. Only a few studies in populations from urban areas have investigated type specific distribution of human papillomavirus (HPV) in Nepali women. Data on high-risk HPV (HR-HPV) types are not currently available for rural populations in Nepal. We aimed to assess the distribution of HR- HPV among rural Nepali women while assessing self-collected and clinician-collected cervico-vaginal specimens as sample collection methods for HPV screening.
Study participants were recruited during a health camp conducted by Nepal Fertility Care Center in Achham District of rural far western Nepal. Women of reproductive age completed a socio-demographic and clinical questionnaire, and provided two specimens; one cervical-vaginal specimen using a self-collection method and another cervical specimen collected by health camp auxiliary nurse midwives during a pelvic examination. All samples were tested for 14 different HR-HPV mRNA and also specific for HPV16/18/45 mRNA.
Of 261 women with both clinician- and self-collected cervical samples, 25 tested positive for HR-HPV, resulting in an overall HR-HPV prevalence of 9.6% (95% confidence Interval [CI]: 6.3–13.8). The overall Kappa value assessing agreement between clinician- and self-collected tests was 0.62 (95% CI: 0.43–0.81), indicating a “good” level of agreement. Abnormal cytology was reported for 8 women. One woman identified with squamous cell carcinoma (SCC), and 7 women with high grade squamous intraepithelial lesions (HSIL). Seven of the 8 women tested positive for HR-HPV (87.5%) in clinician-collected samples and 6 in self-collected samples (75.0%).
This is the first study to assess HR-HPV among rural Nepali women. Self-collected sampling methods should be the subject of additional research in Nepal for screening HR-HPV, associated with pre-cancer lesions and cancer, in women in rural areas with limited access to health services.
PMCID: PMC4076302  PMID: 24978811
25.  Health Promotion for Adolescent Childhood Leukemia Survivors: Building on Prevention Science and eHealth 
Pediatric blood & cancer  2012;60(6):905-910.
Teenage survivors of childhood acute lymphoblastic leukemia (ALL) have increased morbidity likely due to their prior multicomponent treatment. Habits established in adolescence can impact individuals’ subsequent adult behaviors. Accordingly, healthy lifestyles, avoiding harmful actions, and appropriate disease surveillance are of heightened importance among teenage survivors. We review the findings from prevention science and their relevance to heath promotion. The capabilities and current uses of eHealth components including e-learning, serious video games, exergaming, behavior tracking, individual messaging, and social networking are briefly presented. The health promotion needs of adolescent survivors are aligned with those eHealth aspects to propose a new paradigm to enhance the wellbeing of adolescent ALL survivors.
PMCID: PMC4067235  PMID: 23109253
adolescent survivors; prevention science; eHealth; health promotion

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